Keto acids, semialdehydes, and their esters contain two carbonyl moieties, a carboxylate moiety and an oxo moiety. The oxo moiety in keto acids is a ketone, and the oxo moiety in semialdehydes is an aldehyde. Alcohols may react with one or both types of carbonyl moieties. Reaction with the oxo moiety leads to ketal or acetal formation; reaction with the carboxylate moiety leads to ester formation or transesterification. Where it is desirable to react an alcohol with one but not the other carbonyl moiety, selectivity is required to provide good yield of the desired product.
It can be advantageous to react an alcohol with a keto acid, semialdehyde, or ester thereof to form a ketal or an acetal. However, the carboxylic acid or ester moiety present on keto acid and semialdehyde structures presents an additional site for reaction of an alcohol. Where ketal or acetal formation is sought, it is desirable to exclude esterification or transesterification reactions.
The reaction rate of alcohols with oxo moieties to form ketals and acetals is generally slow; for this reason such reactions are typically carried out in the presence of an acid catalyst, most typically homogeneous catalysis is employed using a protic acid (Brønsted-Lowry acid). For example, sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid and mixtures of these are known to catalyze ketal and acetal formation. Lewis acids, e.g. aprotic acids, have also been used to catalyze ketal and acetal formation from alcohols. For example, Clerici et al., Tetrahedron 54, 15679-90 (1998) employ titanium tetrachloride to affect the reaction of methanol with various aldehydes in the presence of ammonia or amine However, the same catalysts employed in ketalization and acetalization reactions are also well known to be catalysts for esterification and transesterification. The conventional amounts of acid employed in the two types of reactions are in the same range when molar equivalents of acid are calculated based on a limiting reagent. Therefore, catalysis of the reaction of an alcohol with a keto acid, semialdehyde, or ester thereof by an acid catalyst can result in esterified side products. For example, three moles of an alcohol such as methanol could react with one mole of a keto acid, such as pyruvic acid, in the presence of a sulfuric acid to yield the dimethyl ketal of methyl pyruvate, or methyl 2,2-dimethoxypropionate.
It is well known that polyhydric alcohols, or polyols, having 1,2 and 1,3 hydroxy conformations can react with a ketone or aldehyde to form a cyclic ketal or an acetal (Carey, F. A. and Sundberg, R. J., “Advanced Organic Chemistry Part B: Reactions and Synthesis” 2nd ed., © 1983, Plenum Press, NY, N.Y., p. 544). The 1,2 and 1,3 configurations of hydroxyl groups on a hydrocarbon chain are shown below as (a) and (b), respectively.
Diols such as 1,2-ethane diol (ethylene glycol) and 1,3 propanediol (propylene glycol) are examples of such polyols. Diols having a 1,2 hydroxyl group configuration will form dioxolanes when reacted with ketone or aldehyde moieties, while 1,3 diols will form dioxanes. Higher polyols, such as triols and tetrols, including polymeric polyols, can be used to form cyclic ketals as well when at least two of the polyol hydroxyl groups are in the 1,2 or 1,3 configuration. Cyclic ketal formation is also typically catalyzed by acids.
Where diols and higher polyols are employed in a ketalization or acetalization reaction of a keto acid, semialdehyde, or an ester thereof, side products can form in addition to the side products resulting from a simple esterification or transesterification. The presence of an acid catalyst can increase the number and concentration of these side products. For example, a diol can undergo esterification or transesterification with the carboxyl moiety of a keto acid, semialdehyde, or ester thereof. The resulting diol ester will have a residual hydroxyl moiety available for either a ketalization/acetalization reaction or further esterification/transesterification. In another example, a triol molecule can react with a keto ester molecule to form the cyclic ketal ester; the cyclic ketal ester will have a residual hydroxyl moiety. Thus, the cyclic ketal ester can undergo further transesterification with another molecule of keto ester or ketal ester. Other side products can form as a result of the acid catalysis of the ketalization/acetalization and esterification/transesterification reactions where triols and higher are employed.
The cyclic ketal of levulinic acid (a keto acid) and glycerol (a triol) is disclosed in U.S. patent application Ser. No. 11/915,549, published as WO 2007/062118, the entire contents of which are incorporated herein by reference. The Application discloses a series of compounds that are based on the initial formation of the cyclic glycerol ketal of levulinic acid, 4-(2-hydroxymethyl-1,4-dioxolan-5-yl) pentanoic acid. The ketalization is carried out using between 0.7 and 1.3 molar equivalents of levulinic acid based on moles of glycerol, further in the presence of 0.0006 to 0.0033 molar equivalents of sulfuric acid based on equivalents of the limiting reagent (whether glycerol or levulinic acid).
Other examples of cyclic ketalization or acetalization reactions of polyols homogeneously catalyzed by protic acid catalysts are found in the literature. For example, F. A. J. Meskens, Synthesis 1981, 501-22, reviews the ketalization of 2,4-dichlorophenacyl chloride with ethylene glycol, catalyzed by p-toluenesulfonic acid monohydrate. The ketalization employs 6 molar equivalents of diol per equivalent of ketone and 0.0077 molar equivalents of catalyst per equivalent of ketone. Yield of the ketal is reported to be 72% after 66 hours reaction time. Hoover, U.S. Pat. No. 1,934,309 discloses the reaction of n-butyl aldehyde with glycerol, catalyzed by sulfuric acid. The acetalization employs a 1:1 molar ratio of triol to aldehyde and 0.0031 molar equivalents of catalyst. Yield is not reported.
Morey, U.S. Pat. No. 2,260,261 discloses the reaction of ethylene glycol, glycerol, and sorbitol with chlorinated acetones. The ketalization of ethylene glycol with 3,3-dichloroacetone is catalyzed by sulfuric acid; the reaction employs 2 molar equivalents of ketone based on diol and 0.0034 molar equivalents of catalyst based on diol, the limiting reagent (or 0.0017 molar equivalents of catalyst based on ketone). The ketalization of glycerol with 3-chlorobutanone is catalyzed by hydrochloric acid; the reaction employs 1.5 molar equivalents of ketone based on triol and 0.0300 molar equivalents of catalyst based on triol, the limiting reagent (or 0.0210 molar equivalents of catalyst based on ketone). And the ketalization of sorbitol with chloroacetone is catalyzed by sulfuric acid; the reaction employs 6.6 molar equivalents of chloroacetone based on hexyl, which corresponds to 2.2 moles of ketone per diol functionality, and 0.0172 molar equivalents of acid based on hexyl, the limiting reagent (corresponding to 0.0057 molar equivalents based on diol functionality, or 0.0026 molar equivalents based on ketone).
Bruchmann et al., U.S. Pat. No. 5,917,059 disclose the reaction of diols and triols, such as glycerol, trimethylolpropane, and ethylene glycol, with an excess of ketone, such as acetone and 2-butanone. The reaction was carried out at reflux, and removal of ketone along with water was remedied by constant addition of additional ketone during the reaction. The ketalization of four moles of ketone with one mole of diol or triol was catalyzed by 0.01 to 0.5 moles of p-toluenesulfonic acid based on moles of alcohol, the limiting reagent. Additional ketone corresponding to 8 to 15 parts by weight of ketone to one part by weight of alcohol was added during the course of the reaction. Eight to twelve hours of reaction time resulted in 97.0% to 99.5% yield of the cyclic ketal.
Other examples of ketalization or acetalization reactions of polyols homogeneously catalyzed by conventional amounts of protic acid catalysts disclose reactions with keto acids. For example, Pasto et al., J. Am. Chem. Soc. 87(7), 1515 (1965) disclose the ketalization of methyl 3-benzoylpropionate with ethylene glycol, catalyzed by p-toluenesulfonic acid. The reaction employs 2.6 molar equivalents of diol based on keto acid and 0.076 molar equivalents of catalyst based on keto acid. Yield is not reported. Ono et al., J. Am. Oil Chem. Soc. 70(1), 29 (1993) disclose ketalization of ethyl pyruvate, ethyl acetoacetate, and ethyl levulinate with various 1-O-alkyl glycerols (diols). The reaction is catalyzed by p-toluenesulfonic acid and employs 1.2 molar equivalents of diol based on moles of keto ester and 0.0500 molar equivalents of catalyst based on moles of ketal ester. Yield is reported to be 96% after two hours of reaction time. McCullough et al., U.S. Pat. No. 5,998,092 disclose the ketalization of two keto acids with ethylene glycol, catalyzed by p-toluenesulfonic acid. The reaction of ethyl 2-(4-vinylbenzyl)-3-oxo-butanoate and ethylene glycol employs 2 molar equivalents of ethylene glycol based on keto ester and 0.0150 molar equivalents of catalyst based on keto ester. Yield is reported to be 81% after 72 hours of reaction time. The reaction of ethyl 2-acetyl-5-hexanoate and ethylene glycol employs 2 molar equivalents of ethylene glycol based on keto ester and 0.0100 molar equivalents of catalyst based on keto ester. Yield is reported to be 81% after 48 hours of reaction time.
Homogeneous acid catalyzed esterification also employs protic acid catalysts, typically in the same range of concentration as the above acetalization and ketalization reactions. For example, ATOFINA Publication No. A-70-1 (© 2001 by Atofina Chemicals, Inc. of Philadelphia, Pa.; available on the internet at http://staging.arkemainc.com/literature/pdf/405.pdf) discloses the esterification of phthalic anhydride with 2-ethylhexanol, employing protic catalysts at various levels. In each case, 2 molar equivalents of alcohol based on phthalic anhydride are employed. Methanesulfonic acid is employed as the catalyst at between 0.0051 and 0.0146 molar equivalents based on alcohol (twice that based on anhydride). Sulfuric acid is employed as the catalyst at between 0.0072 and 0.0143 molar equivalents based on alcohol (twice that based on anhydride). And p-toluenesulfonic acid is employed as the catalyst at between 0.0038 and 0.0074 molar equivalents based on alcohol (twice that based on anhydride). Yields of esterified product ranged from approximately 75% to 97.5% after five hours reaction time. Otera, Esterification, p. 9 (© 2003 Wiley-VCH Verlag GmbH & Co.) discloses a generic esterification procedure for an unspecified carboxylic acid with t-butanol catalyzed by sulfuric acid. The reaction employs 5 molar equivalents of alcohol based on the carboxylic acid and 1 molar equivalent of sulfuric acid based on the carboxylic acid. Yield is not reported. A technical bulletin available from E.I. du Pont de Nemours and Company of Wilmington, Del., “DuPont™ TYZOR® Organic Titanates Technical Note-Direct Esterification” (© 2001 by E.I. du Pont de Nemours and Company) outlines a procedure for esterification of adipic acid with two equivalents of 2-ethylhexyl alcohol catalyzed by sulfuric acid. The reaction employs 0.0089 molar equivalents of catalyst based on adipic acid. Yield is reported to be 100% after 90 minutes reaction time.
While the above references are not exhaustive, they are exemplary in terms of the stoichiometries of reagents employed as well as the amounts and types of acid catalysts used for ketal and acetal formation. The references show that the types and amounts of acid catalysts used for acetalization and ketalization are the same as those employed in esterification reactions. This translates to selectivity issues in selectively forming ketals or acetals in the case of keto acids, semialdehydes, or esters thereof, because esterification or transesterification reactions readily compete with ketalization or acetalization reactions due to the dual functionality of the keto acids and semialdehydes. Particularly where triols and higher polyols are employed in such reactions, side products can form due to the multiple hydroxyl functionality of the polyols and the presence of carboxylic functionality in the keto acid, semialdehyde, or ester thereof as well as the corresponding ketal or acetal product.
When reacting alcohols with keto acids, semialdehydes, and esters thereof, it is desirable to provide selectivity of ketal or acetal formation over esterification or transesterification reactions. It is desirable to reduce the overall concentration of the side products when forming a ketal or acetal of a keto acid, semialdehyde, or ester thereof. It is desirable to reduce the total number of side product species when forming a ketal or acetal of a keto acid, semialdehyde, or ester thereof. It is desirable to accomplish these goals while still retaining the fast reaction rate of ketal or acetal formation afforded by the use of an acid catalyst. It is desirable to employ a reaction methodology that produces high yields of ketal and acetal. It is desirable to employ a reaction methodology that is simple and cost effective.